Expert explores possibility of ‘bradykinin storm’ in lungs of people with COVID-19

A nationally known expert on the inflammatory molecule bradykinin hopes clinical trials will show that attacking it with two medicines already approved by the Food and Drug Administration can help fight severe lung problems linked to COVID-19.

Allen Kaplan, M.D., a professor in the College of Medicine at the Medical University of South Carolina, has been studying bradykinin for decades. His focus has been on bradykinin’s role in hereditary angioedema, a condition that causes severe swelling in the arms, legs, face, stomach and throat.

“Bradykinin acts on small blood vessels, causing them to open up — dilate — but very importantly, become leaky. Fluid leaks into the surrounding tissue,” Kaplan said. That causes swelling in people with angioedema.

But Kaplan now suspects bradykinin may also play a role in the dangerous lung problems that have cropped up in some people with COVID-19. “Sometimes, they say they feel like they’re drowning — they actually have a fluid-like sensation,” he noted.

So what is bradykinin? “It’s a small molecule made up of nine amino acids contained in a larger molecule, a protein. To release the bradykinin, you have to have an enzyme that degrades the protein and liberates the bradykinin.”

If it’s liberated in the lung, the results could be disastrous, unleashing what’s been called a bradykinin storm. “You’re going to get fluid accumulation where you’re trying to breathe in the air — take in the oxygen and get rid of the carbon dioxide. The bradykinin would cause the fluid to leak into the lung spaces including the spaces where gas-air exchange is supposed to occur. If it were bad enough, you would inhibit the transport of oxygen,” Kaplan said.

“It could really be doing a number on the people who have COVID — yet that is a far cry from saying bradykinin is causing the lung problems. Nevertheless, the assumption is really reasonable based on our knowledge of bradykinin.”

Scientific reports that have appeared since the pandemic began support that assumption. “The articles are good and really interesting. Some of them looked at lung fluid, which you can get by a procedure. And in that fluid, they found many of the things that you need to make bradykinin — the enzymes that produce it, the kininogen from which it is derived, the bradykinin receptors,” Kaplan said.

 

“For bradykinin to work, to make the vessels leak, it has to bind to a receptor on the vessel. Almost every element was sky high in those fluids. So that’s exciting for those of us who do research on bradykinin.”

If bradykinin is found to be a culprit in COVID-19 lung problems, there are drugs already approved by the Food and Drug Administration to go after it. 

“One is called icatibant. For bradykinin to work, it has to hit a receptor. The receptor is called B2. Bradykinin has to bind to B2 on the cells that line blood vessels in order to make the vessels leaky. And icatibant binds to the receptor and prevents bradykinin from interacting with it,” Kaplan said.

“There’s also another drug, a monoclonal antibody called lanadelumab that’s given by injection.” Monoclonal antibodies are lab-made antibodies designed to target problematic molecules that trigger unwanted immune reactions.

“What’s exciting to me is one injection of lanadelumab lasts at least two weeks. That’s the critical period when people are sick. It inhibits an enzyme called plasma kallikrein that’s critical for bradykinin formation,” Kaplan said.

He’ll be watching closely as researchers test the medications to see if they’re safe for people with COVID-19 and if they help patients get better. 

If it turns out that bradykinin is, in fact, a key player in COVID’s lung problems, that could open the door to new information about other diseases, too. “The diseases that we know bradykinin is important for very often have swelling associated with them, like hereditary angioedema. It’s usually a skin manifestation, so that it’s visible. But there’s a host of other things that are internal in which bradykinin is suspected but not proven to be a factor,” Kaplan said. 

“If this one turns out, it’s not only going to be important for many lung diseases but other diseases in the body people have been studying for a long time. It could have implications far beyond COVID.”